Neural stimulation system for cardiac fat pads

ABSTRACT

Various aspects relate to a device which, in various embodiments, comprises a header, a neural stimulator, a detector and a controller. The header includes at least one port to connect to at least one lead, and includes first and second channels for use to provide neural stimulation to first and second neural stimulation sites for a heart. The controller is connected to the detector and the neural stimulator to selectively deliver a therapy based on the feedback signal. A first therapy signal is delivered to the first neural stimulation site to selectively control contractility and a second therapy signal is delivered to the second neural stimulation site to selectively control one of a sinus rate and an AV conduction. Other aspects and embodiments are provided herein.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.11/077,583, filed Mar. 11, 2005 now U.S. Pat. No. 7,769,446, which ishereby incorporated by reference in its entirety.

TECHNICAL FIELD

This application relates generally to medical devices and, moreparticularly, to systems, devices and methods to provide neuralstimulation.

BACKGROUND

The automatic nervous system (ANS) regulates “involuntary” organs. TheANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse.” The ANS maintains normal internal function and works with thesomatic nervous system. Autonomic balance reflects the relationshipbetween parasympathetic and sympathetic activity. Changes in autonomicbalance is reflected in changes in heart rate, heart rhythm,contractility, remodeling, inflammation and blood pressure. Changes inautonomic balance can also be seen in other physiological changes, suchas changes in abdominal pain, appetite, stamina, emotions, personality,muscle tone, sleep, and allergies, for example.

Direct stimulation of the vagal parasympathetic fibers has been shown toreduce heart rate via the sympathetic nervous system. In addition, someresearch indicates that chronic stimulation of the vagus nerve may be ofprotective myocardial benefit following cardiac ischemic insult. Reducedautonomic balance (increase in sympathetic and decrease inparasympathetic cardiac tone) during heart failure has been shown to beassociated with left ventricular dysfunction and increased mortality.Research also indicates that increasing parasympathetic tone andreducing sympathetic tone may protect the myocardium from furtherremodeling and predisposition to fatal arrhythmias following myocardialinfarction.

SUMMARY

Various aspects of the present subject matter relate to an implantablemedical device. In various embodiments, the device comprises a header, aneural stimulator, a detector and a controller. The header includes atleast one port to connect to at least one lead, including a firstchannel to connect to a first lead electrode for use to provide neuralstimulation to a first neural stimulation site for a heart, and a secondchannel to connect to a second lead electrode for use to provide neuralstimulation to a second neural stimulation site for the heart. Theneural stimulator is connected to the first channel to selectively applyneural stimulation to the first neural stimulation site for the heart,and is connected to the second channel to selectively apply neuralstimulation to the second neural stimulation site for the heart. Thedetector is connected to the header to receive at least one sensedsignal indicative of at least one sensed physiological parameter. Thedetector is adapted to generate at least one feedback signal based onthe at least one sensed signal. The controller is connected to thedetector and to the neural stimulator to selectively deliver a neuralstimulation therapy based on the feedback signal. The neural stimulationtherapy delivers a first therapy signal through the first channel to thefirst neural stimulation site for the heart to selectively controlcontractility for the heart. The neural stimulation therapy delivers asecond therapy signal through the second channel to the second neuralstimulation site for the heart to selectively control one of a sinusrate and an AV conduction for the heart.

In various device embodiments, the first neural stimulation site for theheart includes an SVC-AO cardiac fat pad located proximate to a junctionbetween a superior vena cava and an aorta, and the second neuralstimulation site for the heart includes a cardiac fat pad selected froma group of fat pads consisting of a PV cardiac fat pad associated withan sinoatrial (SA) node and an IVC-LA cardiac fat pad associated with anatrioventricular (AV) node. The PV cardiac fat pad is located proximateto a junction between a right atrium and right pulmonary vein. TheIVC-LA cardiac fat pad is located proximate to a junction between aninferior vena cava and a left atrium.

Various aspects of the present subject matter relate to a method. Invarious embodiments, the method comprises providing a feedback signalindicative of at least one physiological signal, and providing a neuralstimulation therapy responsive to the feedback signal. In theseembodiments, providing the neural stimulation therapy includesstimulating an SVC-AO cardiac fat pad to selectively controlcontractility for the heart, stimulating a PV cardiac fat pad associatedwith an sinoatrial (SA) node to selectively control a sinus rate, andstimulating an IVC-LA cardiac fat pad associated with anatrioventricular (AV) node to selectively control AV conduction.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C illustrate a heart and are useful to illustrate thephysiology associated with the electrical stimulation of cardiac fatpads to selectively achieve a specific result, such as a selectivechronotropic and/or inotropic result, according to various embodimentsof the present subject matter.

FIG. 2 illustrates a system diagram of an implantable medical deviceembodiment configured for multi-site stimulation and sensing, accordingto various embodiments of the present subject matter.

FIGS. 3 and 4 schematically illustrates various embodiments of animplantable medical device used to selectively apply cardiac neuralstimulation, according to various embodiments of the present subjectmatter.

FIG. 5 illustrates a process flow, according to various embodiments ofthe present subject matter, according to various embodiments of thepresent subject matter.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.Additionally, the identified embodiments are not necessarily exclusiveof each other, as some embodiments may be able to be combined with otherembodiments. The following detailed description is, therefore, not to betaken in a limiting sense, and the scope is defined only by the appendedclaims, along with the full scope of legal equivalents to which suchclaims are entitled.

Examples of Therapeutic Applications

Some embodiments of the present subject matter provide therapies forsituations in which an increase in the amount of sympathetic nervetraffic to the myocardium is needed, such as conditions in which anincrease in heart rate or an increase in the inotropic state of theheart is desirable. Examples of such situations include bradycardia andacute cardiac failure. Selective stimulation of autonomic epicardialganglia can be used to selectively activate the parasympathetic nervoussystem. Embodiments of the present subject matter decrease leftventricular contractility via postganglionic parasympathetic nervoussystem activity. Some embodiments of the present subject matter pace theheart to treat of arrhythmias by stimulating the autonomic nerves ratherthan stimulating the myocardium. Embodiments of the present subjectmatter pace the heart using the autonomic nervous system to providechronotropic and inotropic control via selective cardiac neuralstimulation. The selective neural stimulation provide a natural stimulusfor pacing.

Ischemia, which may occur because of coronary artery disease, can causeincreased sympathetic nervous system activity. This increasedsympathetic activity can result in increased exposure of the myocardiumto epinephrine and norepinephrine. These catecholamines activateintracellular pathways within the myocytes, which lead to myocardialdeath and fibrosis. Stimulation of the parasympathetic nerves inhibitsthe effect from the ischemia-induced increase in sympathetic activity.

Embodiments of the present subject matter selectively stimulate vagalcardial nerves following a myocardial infarction or in heart failurepatients, thus providing a treatment to protect the myocardium fromfurther remodeling and arrhythmogenesis. Embodiments of the presentsubject matter selectively stimulate cardiac sympathetic nervous systemactivity to treat bradycardia or to treat conditions where increasingthe inotropic state of the myocardium is beneficial such as suddencardiac failure, for example.

The intrinsic cardiac ganglionated plexus integrate and process afferentand efferent autonomic nervous system activity. Embodiments of thepresent subject matter stimulation of these pathways to fine-tuneautonomic balance to mitigate a number of cardiovascular disorders. Someembodiments provide selective neural stimulation to increase vagal toneto reduce myocardial exposure to epinephrine, thus reducing myocardialdeath and fibrosis. Some embodiments provide selective neuralstimulation to increase vagal tone to prevent post-MI patients formfurther remodeling or predisposition to fatal arrhythmias. Someembodiments provide selective neural stimulation to provide autonomicbalance following ischemic insult to prevent the onset of lethalarrhythmias. Some embodiments provide selective neural stimulation toprovide specific cardiac pacing effects based on the stimulated fat pad.The selective neural stimulation provides a means for precisely alteringautonomic tone to cardiac tissue while sparing extracardiac effects,such as can occur from stimulation of the vagus nerve trunk. Thus, thepresent subject matter provides means for altering autonomic tone tospecific areas of the heart (e.g. left ventricular contractility).

Examples of Therapeutic Systems

An implantable stimulating electrode is placed near intrinsic autonomiccardiac nerves and ganglia. Some embodiments use epicardial leads forepicardial stimulation of a target neural stimulation site, someembodiments use intravascular leads for transvascular neural stimulationof a target neural stimulation site, and some embodiments useintravascular leads adapted to puncture a vessel for percutaneousstimulation of a target neural stimulation site. An implantable pulsegenerator with programmable pulse generating features is attached to theelectrode. Electrical activation of the electrode(s) stimulates thetarget sympathetic or parasympathetic nerves anatomically located nearthe electrode(s) at a strength and frequency sufficient to elicitdepolarization of the adjacent nerve(s) while sparing the underlyingmyocardium.

Some embodiments electrically stimulate autonomic nerves innervating themyocardium without eliciting depolarization and contraction of themyocardium directly because the threshold for neural depolarization(especially myelinated vagal nerve fibers of the parasympathetic nervoussystem) is much lower than that of myocardial tissue. Differingfrequencies of stimulation can be used so as to depolarize post (or prein case of vagal nerve stimulation) ganglionic nerve fibers. A stimulusresponse curve may be generated to determine the minimal thresholdrequired to elicit myocardial contraction, and still maintain neuraldepolarization of the site. Some embodiments time the neural stimulationwith the refractory period.

Stimulation can be combined with sensor technology, and may occur duringcombinations of pacing parameters to get selective effects. Someembodiments adjust parameters of the neural stimulation to elicitselective effects. For example, the strength of the parasympatheticresponse can be modulated by adjusting the amplitude of a neuralstimulation signal. However, judicious selection of stimulationfrequency can either activate the parasympathetic pathway or block thebaseline level of parasympathetic activity, causing the oppositephysiological effect. The neural stimulation can be applied duringcardiac pacing to elicit selective effects. For example, ifcontractility modulation is desired, fat pad stimulation can be appliedduring pacing to achieve contractility effects without rate effects.

Some embodiments stimulate an SVC-AO cardiac fat pad located proximateto a junction between a superior vena cava and an aorta. Stimulation ofthe SVC-AO fat pad specifically reduces the contractility of the leftventricle, thus providing a neural stimulation treatment for diseasessuch as heart failure and/or post myocardial infarction remodeling. Someembodiments stimulate a PV cardiac fat pad associated with an sinoatrial(SA) node and some embodiments stimulate an IVC-LA cardiac fat padassociated with an atrioventricular (AV) node. The PV cardiac fat pad islocated proximate to a junction between a right atrium and rightpulmonary vein, and the IVC-LA cardiac fat pad is located proximate to ajunction between an inferior vena cava and a left atrium. Stimulation ofthe PV cardiac fat pad reduces a sinus rate, and stimulation of theIVC-LA fat pad increases AV conduction, which affects timing between acontractions in a right atrium and contractions in the right ventricle.Fat pad stimulation activates parasympathetic efferents. Because fat padganglia form part of the efferent pathway, stimulation of cardiac fatpads directly effects cardiac tissue. For example, stimulating theparasympathetic efferents can selectively affect rate, and conduction.Stimulation of the parasympathetic also has post-ganglionic inhibitionof sympathetic outflow.

Leads are used to deliver the selective neural stimulation to a cardiacneural stimulation site. Lead embodiments include epicardial leads andintravascularly-fed leads. Various lead embodiments are designed andpositioned to provide multiple effects, sensing, pacing ICD etc. inaddition to neural stimulation. The present subject matter uses anepicardial, transvascular and/or percutaneous approaches to elicitadjacent neural depolarization, thus avoiding direct neural contact witha stimulating electrode and reducing problems associated with neuralinflammation and injury associated with direct contact electrodes.

Autonomic Nervous System

The automatic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes, but is not limited to, the sympathetic nervous systemand the parasympathetic nervous system. The sympathetic nervous systemis affiliated with stress and the “fight or flight response” toemergencies. Among other effects, the “fight or flight response”increases blood pressure and heart rate to increase skeletal muscleblood flow, and decreases digestion to provide the energy for “fightingor fleeing.” The parasympathetic nervous system is affiliated withrelaxation and the “rest and digest response” which, among othereffects, decreases blood pressure and heart rate, and increasesdigestion to conserve energy. The ANS maintains normal internal functionand works with the somatic nervous system.

Stimulating the sympathetic and parasympathetic nervous systems can havea number of physiological effects. For example, stimulating thesympathetic nervous system dilates the pupil, reduces saliva and mucusproduction, relaxes the bronchial muscle, reduces the successive wavesof involuntary contraction (peristalsis) of the stomach and the motilityof the stomach, increases the conversion of glycogen to glucose by theliver, decreases urine secretion by the kidneys, and relaxes the walland closes the sphincter of the bladder. Stimulating the parasympatheticnervous system (inhibiting the sympathetic nervous system) constrictsthe pupil, increases saliva and mucus production, contracts thebronchial muscle, increases secretions and motility in the stomach andlarge intestine, and increases digestion in the small intention,increases urine secretion, and contracts the wall and relaxes thesphincter of the bladder. The functions associated with the sympatheticand parasympathetic nervous systems are many and can be complexlyintegrated with each other. Thus, an indiscriminate stimulation of thesympathetic and/or parasympathetic nervous systems to achieve a desiredresponse, such as vasodilation, in one physiological system may alsoresult in an undesired response in other physiological systems. Toavoided these undesired effects, embodiments of the present subjectmatter provide neural stimulation to cardiac nerves to selectivelyachieve a specific result.

Cardiac Physiology

FIGS. 1A-1C illustrate a heart and are useful to illustrate thephysiology associated with the electrical stimulation of cardiac fatpads to selectively achieve a specific result, such as a selectivechronotropic and/or inotropic result, according to embodiments of thepresent subject matter. The illustrated heart 100 includes a rightatrium 102, a right ventricle 104, a left atrium 106 and a leftventricle 108. The illustrated heart 100 also includes a sinoatrial (SA)node 110 and an atrioventricular (AV) node 112. FIG. 1A illustrates thecardiac conduction system which controls heart rate. This systemgenerates electrical impulses and conducts them throughout the muscle ofthe heart to stimulate the heart to contract and pump blood. The cardiacconduction system includes the SA node 110 and the AV node 112. Theautonomic nervous system controls the firing of the SA node to triggerthe start of the cardiac cycle. The SA node includes a cluster of cellsin the right atrium that generates the electrical impulses. Theelectrical signal generated by the SA node moves from cell to cell downthrough the heart until it reaches the AV node 112, a cluster of cellssituated in the center of the heart between the atria and ventricles.The AV node functions as an electrical relay station between the atriaand the ventricles, such that electrical signals from the atria mustpass through the AV node to reach the ventricles. The AV node slows theelectrical current before the signal is permitted to pass down throughto the ventricles, such that the atria are able to fully contract beforethe ventricles are stimulated. After passing the AV node, the electricalcurrent travels to the ventricles along special fibers 114 embedded inthe walls of the lower part of the heart.

FIGS. 1B and 1C illustrate other views a heart, including epicardial fatpads that function as target cardiac neural stimulation sites. FIGS. 1Band 1C illustrate the right side and left side of the heart,respectively.

FIG. 1B illustrates the right atrium 102, right ventricle 104, SA node110, superior vena cava 118, inferior vena cava 120, aorta 122, rightpulmonary veins 124, and right pulmonary artery 126. FIG. 1B alsoillustrates a cardiac fat pad 128, referred to herein as the SVC-AO fatpad, between the superior vena cava and aorta. Nerve endings in theSVC-AO cardiac fat pad 128 are stimulated in some embodiments using anelectrode screwed into or otherwise placed in the fat pad, and arestimulated in some embodiments using an intravenously-fed leadproximately positioned to the fat pad in a vessel such as the rightpulmonary artery 126 or superior vena cava 118, for example. Someembodiments use an intravascularly-fed lead adapted to puncture througha vessel wall to place an electrode proximate to a target neuralstimulation site. An example of such a lead is provided in U.S. patentapplication Ser. No. 11/077,970, filed on Mar. 11, 2005, which is hereinincorporated by reference in its entirety.

FIG. 1C illustrates the left atrium 106, left ventricle 108, rightatrium 102, right ventricle 104, superior vena cava 118, inferior venacava 120, aorta 122, right pulmonary veins 130, left pulmonary vein 132,right pulmonary artery 134, and coronary sinus 136. FIG. 1C alsoillustrates a cardiac fat pad 138, referred to herein as the PV fat pad,located proximate to a junction between the right atrium and rightpulmonary veins and a cardiac fat pad 116, referred to herein as theIVC-LA fat pad, located proximate to or at the junction of the inferiorvena cava and left atrium. Nerve endings in the PV fat pad 138 arestimulated in some embodiments using an electrode screwed into the fatpad 138, and are stimulated in some embodiments using anintravenously-fed lead proximately positioned to the fat pad in a vesselsuch as the right pulmonary artery 134 or right pulmonary vein 130, forexample. Some embodiments use an intravascularly-fed lead adapted topuncture through a vessel wall to place an electrode proximate to atarget neural stimulation site.

FIG. 1C also illustrates a cardiac fat pad 116, referred to herein asthe IVC-LA fat pad, located proximate to a junction between the inferiorvena cava 120 and the left atrium 106. Nerve endings in the IVC-LA fatpad 116 are stimulated in some embodiments using an electrode screwedinto the fat pad using either an epicardial or intravascular lead, andare transvascularly stimulated in some embodiments using anintravascular electrode proximately positioned to the fat pad in avessel such as the inferior vena cava 120 or coronary sinus 136 or alead in the left atrium 106, for example. Some embodiments use anintravascularly-fed lead adapted to puncture through a vessel wall toplace an electrode proximate to a target neural stimulation site.

The function of the SVC-AO fat pad, positioned between the medialsuperior vena cava and aortic root superior to the right pulmonaryartery, has been identified as a “head station” of vagal fibersprojecting to both atria and to the IVC-LA and PV fat pads.

The nervous system regulating the rhythm of the heart includes a numberof ganglionated fat pads. Parasympathetic ganglia is these discreteepicardial fat pads exert important effects on chronotropy, dromotropyand inotropy.

The PV fat pad is associated with the SA node, and the IVC-LA fat pad isassociated with the AV node. Stimulation of the PV fat pad associatedwith the SA node provides direct vagal inhibition of the SA node,resulting in slowing of the sinus rate without prolonging AV conductiontime. The IVC-LA fat pad selectively innervates the AV nodal region andregulates AV conduction. Stimulation of the IVC-LA fat pad extends theAV conduction time without slowing of the sinus rate.

Disruption of neural activity in the fat pads can cause significantheterogeneity of repolarization, and tend to result in atrialarrhythmias. An intrinsic cardiac neuronal network is important to bothintracardiac and extracardiac integration of autonomic control ofcardiac function. Unfortunately, this cardiac neuronal network can bedamaged, thus adversely affecting the autonomic balance.

Myocardial ischemia can compromise the function of cardiac intrinsicneurons embedded with the fat pads, potentially inducing arrhythmias.Diabetic neuropathy affecting intrinsic cardiac innervation can alsoenhance susceptibility to arrhythmias. Surgery and ablation proceduresmay sever or otherwise damage a portion of the cardiac neuronal network,thus damaging heart rhythm control.

Cardiac performance depends on heart rate, preload, afterload andcontractility. The following provides one representation for cardiacperformance:Cardiac Output=Heart Rate×Stroke Volume

Stroke volume depends on preload, the left ventricular end diastolicvolume related to the amount of stretch in the left ventricle stretch.Stroke volume also depends on afterload, the total peripheralresistance. Contractility relates to the ability of the heart muscle toshorten which relates to the ability of the myocardium to respond topreload and afterload. Increased contractility has a positive inotropiceffect, being associated with increased stroke volume and ejectionfraction. Decreased contractility is associated with decreased strokevolume and ejection fraction. Contractility is increased by sympatheticdischarge to the ventricles, circulating epinephrine, and faster heartrates. Cardiac performance may be defined by a number of differentparameters that tend to be interrelated to some degree. Performanceparameters include, but are not limited to, stroke volume, stroke work,rate of shortening for the muscle fibers, cardiac output and ejectionfraction. Thus, a number of sensors can be used to provide either adirect or indirect indicator of contractility. Ejection fraction relatesto the portion of blood that is pumped out of a filled ventricle as aresult of a heartbeat. The heart normally pumps out or ejects abouttwo-thirds of the blood with each beat. The ejection fraction is anindicator of the heart's health. If the heart is diseased from a heartattack or another cardiac condition, the ejection fraction may fall, forexample, to a third.

Cardiac rate, AV conduction, and contractility are mediated throughganglia located in cardiac fat pads. Data indicates that specificganglia selectively mediates cardiac rate, AV conduction, andcontractility. Sympathetic neural stimulation directly increasescontractility, indirectly increases preload and afterload. Embodimentsof the present subject provide specific cardiac neural stimulation toachieve a desired local effect, such as increasing ventricularcontractility without increasing heart rate or inducing an arrhythmia,for example. Embodiments of the present subject matter selectivelystimulate cardiac fat pads to selectively control contractility for theheart, sinus rate and AV conduction. Embodiments of the present subjectmatter control the stimulation with feedback signals indicative ofcontractility, sinus rate and/or AV conduction.

Examples of sensors that are capable of providing a feedback signalcapable of being indicative of cardiac contractility include sensors todirectly measure or sense contractility, and sensors to indirectlymeasure or sense contractility. An example of a sensor to directlymeasure contractility is a strain gauge. An example of a sensor toindirectly measure contractility is a sensor to measure cardiac output.

Examples of sensors that are capable of providing a feedback signalcapable of being indicative of a sinus rate include electrode(s)positioned proximate to the sinoatrial (SA) node and cooperating sensingcircuitry connected to the electrode(s) to detect intrinsic events nearthe SA node. Rate can be sensed using electrograms, leadless ECGelectrodes on the can of the implantable device, flow sensors, and heartsounds using a vibration sensor/accelerometer, for example.

Examples of sensors that are capable of providing a feedback signalcapable of being indicative of an atrioventricular (AV) conductioninclude an electrode positioned in or proximate to a right atrium, anelectrode positioned in or proximate to a right ventricle, andcooperating sensing circuitry connected to the electrodes to detectintrinsic events on each side of the AV node. AV conduction can besensed using dual chamber electrograms, leadless ECG electrodes on thecan of the implantable device, and heart sounds, which may be used todetect AV dyssynchrony.

Implantable Medical Device Embodiments

Implantable cardiac devices that provide electrical stimulation toselected chambers of the heart have been developed in order to treat anumber of cardiac disorders. A pacemaker, for example, is a device whichpaces the heart with timed pacing pulses, most commonly for thetreatment of bradycardia where the ventricular rate is too slow. AVconduction defects (i.e., AV block) and sick sinus syndrome representthe most common causes of bradycardia for which permanent pacing may beindicated. If functioning properly, the pacemaker makes up for theheart's inability to pace itself at an appropriate rhythm in order tomeet metabolic demand by enforcing a minimum heart rate. Implantabledevices may also be used to treat cardiac rhythms that are too fast,with either anti-tachycardia pacing or the delivery of electrical shocksto terminate fibrillation.

Implantable devices have also been developed that affect the manner anddegree to which the heart chambers contract during a cardiac cycle inorder to promote the efficient pumping of blood. The heart pumps moreeffectively when the chambers contract in a coordinated manner, a resultnormally provided by the specialized conduction pathways in both theatria and the ventricles that enable the rapid conduction of excitation(i.e., depolarization) throughout the myocardium. These pathways conductexcitatory impulses from the SA node to the atrial myocardium, to the AVnode, and thence to the ventricular myocardium to result in acoordinated contraction of both atria and both ventricles. This bothsynchronizes the contractions of the muscle fibers of each chamber andsynchronizes the contraction of each atrium or ventricle with thecontralateral atrium or ventricle. Without the synchronization affordedby the normally functioning specialized conduction pathways, the heart'spumping efficiency is greatly diminished. Pathology of these conductionpathways and other inter-ventricular or intra-ventricular conductiondeficits can be a causative factor in heart failure, which refers to aclinical syndrome in which an abnormality of cardiac function causescardiac output to fall below a level adequate to meet the metabolicdemand of peripheral tissues. In order to treat these problems,implantable cardiac devices have been developed that provideappropriately timed electrical stimulation to one or more heart chambersin an attempt to improve the coordination of atrial and/or ventricularcontractions, termed cardiac resynchronization therapy (CRT).Ventricular resynchronization is useful in treating heart failurebecause, although not directly inotropic, resynchronization can resultin a more coordinated contraction of the ventricles with improvedpumping efficiency and increased cardiac output. Currently, a commonform of CRT applies stimulation pulses to both ventricles, eithersimultaneously or separated by a specified biventricular offsetinterval, and after a specified AV delay interval with respect to thedetection of an intrinsic atrial contraction or delivery of an atrialpace.

Embodiments of the present subject matter provide selective cardiacneural stimulation to pace the heart, improve contractility and thusprovide a natural stimulus to improve pumping efficiency and cardiacoutput. For example, the PV fat pad is stimulated to control sinus rate,the IVC-LA fat pad is stimulated to control AV conduction, and theSVC-AO fat pad is stimulated to control contractility.

FIG. 2 illustrates a system diagram of an implantable medical deviceembodiment configured for multi-site stimulation and sensing. Pacing, asused in the discussion of this figure, relates to electricalstimulation. In various embodiments, the stimulation for a given channelincludes stimulation to capture myocardia, neural stimulation or bothpacing and neural stimulation. Three exemplary sensing and pacingchannels designated “A” through “C” comprise bipolar leads with ringelectrodes 250A-C and tip electrodes 251A-C, sensing amplifiers 252A-C,pulse generators 253A-C, and channel interfaces 254A-C. Each of thesechannels thus includes a stimulation channel extending between the pulsegenerator, the electrode and a sensing channel extending between thesense amplifier and the electrode. The channel interfaces 254A-Ccommunicate bidirectionally with microprocessor 255, and each interfacemay include analog-to-digital converters for digitizing sensing signalinputs from the sensing amplifiers and registers that can be written toby the microprocessor in order to output pacing pulses, change thepacing pulse amplitude, and adjust the gain and threshold values for thesensing amplifiers. The sensing circuitry detects a chamber sense,either an atrial sense or ventricular sense, when an electrogram signal(i.e., a voltage sensed by an electrode representing cardiac electricalactivity) generated by a particular channel exceeds a specifieddetection threshold. Algorithms used in particular stimulation modesemploy such senses to trigger or inhibit stimulation, and the intrinsicatrial and/or ventricular rates can be detected by measuring the timeintervals between atrial and ventricular senses, respectively. The AVconduction can be measured by measuring a time interval between atrialand ventricular intrinsic events. According to various embodiments, thepulse generator is adapted to vary parameters of a neural stimulationsignal, such as amplitude, frequency and duty cycle, for example.

The switching network 256 is used to switch the electrodes to the inputof a sense amplifier in order to detect intrinsic cardiac activity andto the output of a pulse generator in order to deliver stimulation. Theswitching network also enables the device to sense or stimulate eitherin a bipolar mode using both the ring and tip electrodes of a lead or ina unipolar mode using only one of the electrodes of the lead with thedevice housing or can 257 serving as a ground electrode or anotherelectrode on another lead serving as the ground electrode. A shock pulsegenerator 258 is also interfaced to the controller for delivering adefibrillation shock via a pair of shock electrodes 259 to the atria orventricles upon detection of a shockable tachyarrhythmia. Channelinterface 265 and sense amplifier 264 provide a connection between themicroprocessor and the switch to receive a sensed signal fromphysiological sensor 262 for use as a feedback control signal indicativeof the efficacy of the stimulation therapy. Various embodiments sensephysiological parameters associated with sinus rate, AV conductionand/or contractility. Examples of sensors to provide such a feedbackinclude, but are not limited to, sensors to detect heart rate, sensorsto detect blood pressure, sensors to detect blood flow, sensors todetect respiration and sensors to detect cardiac output.

The controller or microprocessor controls the overall operation of thedevice in accordance with programmed instructions stored in memory 260,including controlling the delivery of stimulation via the channels,interpreting sense signals received from the sensing channels, andimplementing timers for defining escape intervals and sensory refractoryperiods. The controller is capable of operating the device in a numberof programmed stimulation modes which define how pulses are output inresponse to sensed events and expiration of time intervals. Mostpacemakers for treating bradycardia are programmed to operatesynchronously in a so-called demand mode where sensed cardiac eventsoccurring within a defined interval either trigger or inhibit a pacingpulse. Inhibited stimulation modes utilize escape intervals to controlpacing in accordance with sensed intrinsic activity such that astimulation pulse is delivered to a heart chamber during a cardiac cycleonly after expiration of a defined escape interval during which nointrinsic beat by the chamber is detected. Escape intervals forventricular stimulation can be restarted by ventricular or atrialevents, the latter allowing the pacing to track intrinsic atrial beats.A telemetry interface 261 is also provided which enables the controllerto communicate with an external programmer or remote monitor. Someembodiments incorporate sensor channels into the device for receivingsignals indicative of sense physiological parameters, such as parametersindicative of contractility, AV conduction and/or sinus rate.

FIGS. 3 and 4 schematically illustrates various embodiments of animplantable medical device used to selectively apply cardiac neuralstimulation. The illustrated medical devices of FIGS. 4A-4B includechannels, as generally illustrated in FIG. 3, but are illustrated withfunctional blocks to further illustrate the present subject matter.

FIG. 3 illustrates an implantable medical device. The illustrated device340 includes a pulse generator 366 and a header 367. The header 367includes at least one port 368 to receive at least one lead 369 that hasat least one electrode. In some embodiments, the lead includes a sensorto detect physiological parameters other than intrinsic electricalsignals sensed by electrodes. The header 367 functions as an interfacebetween the lead(s) 369 and the pulse generator 366. The illustratedpulse generator includes a controller 370 connected to a memory 360 anda telemetry interface 361 to communicate with an external programmer.The controller 370 is connected to a neural stimulator 371 and adetector 372. The neural stimulator is adapted to provide a first neuralstimulation therapy at a first cardiac neural stimulation site, a secondneural stimulation therapy at a second cardiac neural stimulation site,and a third neural stimulation therapy at a third cardiac neuralstimulation site. The detector 372 is adapted to receive a signalindicative of physiological parameter or parameters, and provide afeedback signal to the controller 370 based on the received signal.Examples of sensed physiological parameters include, but are not limitedto, heart rate, blood pressure, blood flow, respiration and cardiacoutput.

The circuits or modules 371 and 372 appropriately interface with theelectrode(s), and in some embodiments other sensors, on the lead(s) viaswitches 356 (e.g. MOS switches). The switches provide logicalconnections that allow circuits 371 and 372 to connect to a desired port368 to access a desired channel on a desired lead. FIG. 3 illustratescircuits 371 and 372 distinct from controller 370. As will be understoodby those of ordinary skill in the art upon reading and comprehendingthis disclosure, various functions associated with circuits 371 and 372can be integrated with controller 370 in various embodiments.

FIG. 4 illustrates an implantable medical device. The device of FIG. 4generally corresponds to the device in FIG. 3, adding further detailaccording to an embodiment of the present subject matter. For the sakeof clarity, FIG. 4 illustrates connections between circuits 471 and 472to ports 468A, 468B, 468C and 468D. The illustrated device 440 includesa pulse generator 466 and a header 467.

The illustrated header 467 includes an SVC-AO port 468A to receive anSVC-AO lead 469A with at least one electrode to stimulate the SVC-AO fatpad. The illustrated header 467 further includes a PV port 468B toreceive a PV lead 469B with at least one electrode to stimulate the PVfat pad. The illustrated header 467 further includes an IVC-LA port 468Cto receive an IVC-LA lead 469C with at least one electrode to stimulatethe IVC-LA fat pad. The illustrated header 467 further includes a sensorport 468D to receive sensor lead 469D with at least one sensor to sensea physiological signal indicative of the efficacy of the neural therapyto provide closed loop feedback control. The leads 469A, 469B, and 469Ccan be epicardial leads, intravascular leads for transvascularstimulation of a neural stimulation site outside of the vessel, orintravascular leads for puncturing a vessel for placement of anelectrode(s) proximate to a neural stimulation site outside of thevessel. Additionally, a lead can be designed to combine functionsassociated with two or more leads into one lead.

The header 467 functions as an interface between the lead(s) and thepulse generator 466. The illustrated pulse generator includes acontroller 470 connected to a memory 460 and a telemetry interface 461to communicate with an external programmer. The controller 470 isconnected to a neural stimulator 471 and a detector 472. The neuralstimulator is adapted to provide a neural stimulation therapy to controlcontractility by stimulating an SVC-AO fat pad, a neural stimulationtherapy to control sinus rate by stimulating a PV fat pad, and a neuralstimulation therapy to control AV conduction by stimulating an IVC-LAfat pad. The detector 472 is adapted to receive a signal indicative ofphysiological parameter or parameters, and provide a feedback signal tothe controller 470 based on the received signal. According to variousembodiments, the detector 472 is adapted to receive a signal and providea corresponding feedback signal to the controller that is indicative ofa sinus rate, an AV conduction and contractility.

FIG. 5 illustrates a process flow, according to various embodiments ofthe present subject matter. Beginning at 590, the illustrated processprovides neural stimulation therapy at 591 and provides feedback at 592for closed loop control of the neural stimulation therapy. Theillustrated neural stimulation therapy includes stimulation of a firstsite (e.g. 593) and stimulation of a second site (e.g. 594 or 595) tocontrol chronotropic and inotropic parameters. The illustrated neuralstimulation therapy also includes a more detailed embodiment in which anSVC-AO cardiac fat pad is stimulated at 593 to selectively controlcontractility for the heart, a PV cardiac fat pad associated with ansinoatrial (SA) node is stimulated at 594 to selectively control a sinusrate, and an IVC-LA cardiac fat pad associated with an atrioventricular(AV) node is stimulated at 595 to selectively control AV conduction. Asillustrated in FIG. 5, the feedback is based on physiological parameters596 that provide an indication of one or more of the sinus rate, the AVconduction and contractility. In some embodiments, the process flow isstored as computer instructions in memory (e.g. 360 in FIG. 3 and 460 inFIG. 4) and is operated on by the controller (e.g. 370 in FIG. 3 and 470in FIG. 4) to perform the process.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the term module is intended to encompass software implementations,hardware implementations, and software and hardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. In variousembodiments, the methods provided above are implemented as a computerdata signal embodied in a carrier wave or propagated signal, thatrepresents a sequence of instructions which, when executed by aprocessor cause the processor to perform the respective method. Invarious embodiments, methods provided above are implemented as a set ofinstructions contained on a computer-accessible medium capable ofdirecting a processor to perform the respective method. In variousembodiments, the medium is a magnetic medium, an electronic medium, oran optical medium.

Although specific embodiments have been illustrated and describedherein, it will be appreciated by those of ordinary skill in the artthat any arrangement which is calculated to achieve the same purpose maybe substituted for the specific embodiment shown. This application isintended to cover adaptations or variations of the present subjectmatter. It is to be understood that the above description is intended tobe illustrative, and not restrictive. Combinations of the aboveembodiments as well as combinations of portions of the above embodimentsin other embodiments will be apparent to those of skill in the art uponreviewing the above description. The scope of the present subject mattershould be determined with reference to the appended claims, along withthe full scope of equivalents to which such claims are entitled.

1. A method, comprising: providing a feedback signal indicative of at least one physiological signal; and providing a neural stimulation therapy responsive to the feedback signal, wherein providing the neural stimulation therapy includes: stimulating an SVC-AO cardiac fat pad to change ventricular contractility of the heart without changing heart rate or inducing an arrhythmia, the SVC-AO fat pad being located proximate to a junction between a superior vena cava and an aorta; and stimulating: a PV cardiac fat pad associated with an sinoatrial (SA) node to change a sinus rate of the heart without changing AV conduction time, the PV cardiac fat pad being located proximate to a junction between a right atrium and right pulmonary veins; or an IVC-LA cardiac fat pad associated with an atrioventricular (AV) node to change the AV conduction time of the heart without changing the sinus rate, the IVC-LA cardiac fat pad being located proximate to a junction between an inferior vena cava and a left atrium.
 2. The method of claim 1, wherein providing a neural stimulation therapy includes using an epicardial lead to epicardially stimulate at least one of the cardiac fat pads.
 3. The method of claim 1, wherein providing a neural stimulation therapy includes using an intravascularly-fed lead to transvascularly stimulate at least one of the cardiac fat pads.
 4. The method of claim 3, wherein using an intravascularly-fed lead to transvascularly stimulate at least one of the cardiac fat pads includes using a lead configured to be fed into a right pulmonary artery to stimulate the SVC-AO cardiac fat pad.
 5. The method of claim 3, wherein using an intravascularly-fed lead to transvascularly stimulate at least one of the cardiac fat pads includes using a lead configured to be fed into the superior vena cava to stimulate the SVC-AO cardiac fat pad.
 6. The method of claim 3, wherein using an intravascularly-fed lead to transvascularly stimulate at least one of the cardiac fat pads includes using a lead configured to be fed into the right pulmonary artery to stimulate the PV cardiac fat pad.
 7. The method of claim 3, wherein using an intravascularly-fed lead to transvascularly stimulate at least one of the cardiac fat pads includes using a lead configured to be fed into the right pulmonary vein to stimulate the PV cardiac fat pad.
 8. The method of claim 3, wherein using an intravascularly-fed lead to transvascularly stimulate at least one of the cardiac fat pads includes using a lead configured to be fed into the interior vena cava to stimulate the IVC-LA cardiac fat pad.
 9. The method of claim 3, wherein using an intravascularly-fed lead to transvascularly stimulate at least one of the cardiac fat pads includes using a lead configured to be fed into a coronary sinus to stimulate the IVC-LA cardiac fat pad.
 10. The method of claim 3, wherein using an intravascularly-fed lead to transvascularly stimulate at least one of the cardiac fat pads includes using a lead configured to be fed into the left atrium to stimulate the IVC-LA cardiac fat pad.
 11. The method of claim 1, wherein providing a feedback signal includes providing a feedback signal indicative of the ventricular contractility.
 12. The method of claim 1, wherein the IVC-LA cardiac fat pad associated with the AV node is stimulated, and providing a feedback signal includes providing a feedback signal indicative of the AV conduction time.
 13. The method of claim 1, wherein the PV cardiac fat pad associated with the SA node is stimulated, and providing a feedback signal includes providing a feedback signal indicative of the sinus rate.
 14. The method of claim 1, wherein providing a neural stimulation therapy includes using neural stimulation to provide specific pacing effects to change: ventricular contractility of the heart without changing heart rate or inducing an arrhythmia; and a sinus rate of the heart without changing AV conduction time, or the AV conduction time of the heart without changing the sinus rate.
 15. A method, comprising: providing a feedback signal indicative of at least one physiological signal; and providing a neural stimulation therapy responsive to the feedback signal, including: stimulating an SVC-AO cardiac fat pad to change ventricular contractility of the heart without changing heart rate or inducing an arrhythmia, the SVC-AO fat pad being located proximate to a junction between a superior vena cava and an aorta; and stimulating a PV cardiac fat pad associated with an sinoatrial (SA) node to change a sinus rate of the heart without changing AV conduction time, the PV cardiac fat pad being located proximate to a junction between a right atrium and right pulmonary veins; and stimulating an IVC-LA cardiac fat pad associated with an atrioventricular (AV) node to change the AV conduction time of the heart without changing the sinus rate, the IVC-LA cardiac fat pad being located proximate to a junction between an inferior vena cava and a left atrium.
 16. The method of claim 15, wherein providing a neural stimulation therapy includes using an epicardial lead to epicardially stimulate at least one of the cardiac fat pads.
 17. The method of claim 15, wherein providing a neural stimulation therapy includes using an intravascularly-fed lead to transvascularly stimulate at least one of the cardiac fat pads.
 18. The method of claim 15, wherein providing a feedback signal indicative of at least one physiological signal includes providing a cardiac rate feedback signal.
 19. The method of claim 15, wherein providing a feedback signal indicative of at least one physiological signal includes providing a cardiac rhythm feedback signal.
 20. The method of claim 15, wherein providing a feedback signal indicative of at least one physiological signal includes providing a cardiac contractility feedback signal.
 21. The method of claim 15, wherein providing a feedback signal indicative of at least one physiological signal includes providing a blood pressure feedback signal.
 22. The method of claim 1, wherein providing a neural stimulation therapy includes using neural stimulation to provide specific pacing effects to change ventricular contractility of the heart without changing heart rate or inducing an arrhythmia, change a sinus rate of the heart without changing AV conduction time, and change the AV conduction time of the heart without changing the sinus rate.
 23. A method for providing specific pacing effects to a heart, comprising: changing ventricular contractility of the heart without changing heart rate or inducing an arrhythmia; and changing a sinus rate or an AV conduction time of the heart, wherein changing the sinus rate does not change the AV conduction time and changing the AV conduction does not change the sinus rate, wherein changing the ventricular contractility includes stimulating an SVC-AO cardiac fat pad located proximate to a junction between a superior vena cava and an aorta, wherein changing the sinus rate includes stimulating a PV cardiac fat pad located proximate to a junction between a right atrium and right pulmonary veins, and wherein changing the AV conduction time includes stimulating an IVC-LA cardiac fat pad located proximate to a junction between an inferior vena cava and a left atrium. 